What is the most effective Disease-Modifying Antirheumatic Drug (DMARD) for inflammation, Arava (Leflunomide) versus Methotrexate?

From the Guidelines

Methotrexate is generally considered the first-line DMARD for treating inflammatory conditions like rheumatoid arthritis due to its established efficacy, extensive safety data, and lower cost, as supported by the most recent study 1.

Key Points to Consider

• Methotrexate typically starts at 7.5-10mg weekly, gradually increasing to 15-25mg weekly as needed, with folic acid supplementation (1mg daily) to reduce side effects.
• Leflunomide is often used when methotrexate is not tolerated or ineffective, starting with a loading dose of 100mg daily for 3 days followed by 20mg daily maintenance (or sometimes 10mg daily if side effects occur).
• Methotrexate works by inhibiting dihydrofolate reductase and promoting adenosine release, while leflunomide inhibits pyrimidine synthesis by blocking dihydroorotate dehydrogenase.
• Both medications require regular monitoring of liver function, complete blood counts, and kidney function.
• The choice between these medications should be individualized based on patient factors including comorbidities, pregnancy plans (both are contraindicated), and tolerance of side effects.

Supporting Evidence

• A 2019 study 1 conditionally recommends methotrexate over leflunomide and sulfasalazine for patients with juvenile idiopathic arthritis and polyarthritis, citing the greater volume of data supporting methotrexate's effectiveness.
• Earlier studies 1 also support methotrexate as a first-line DMARD due to its efficacy, safety profile, and ability to be combined with biological treatments.
• The optimal dosage and route of administration of methotrexate have been studied, with recommendations for starting at 15mg/week orally and escalating to 25-30mg/week as needed, with a switch to subcutaneous administration if necessary 1.
• EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs also support the use of methotrexate as a first-line treatment 1.

From the FDA Drug Label

Table 6 Summary of ACR Response Rates * N is the number of ITT patients for whom adequate data were available to calculate the indicated rates. † p<0.001 leflunomide vs placebo Study and Treatment Group ACR20 ACR50 ACR70 Placebo-Controlled Studies US301 (12 months) Leflunomide (n=178)* 52.2† 34.3† 20.2† Placebo (n=118)*26.3 7.6 4.2 Methotrexate (n=180)45.622.8 9.4 MN301 (6 months) Leflunomide (n=130) 54. 6† 33.1† 10.0 Placebo (n=91)*28.614.3 2.2 Sulfasalazine (n=132)*56.830.3 7.6 Non-Placebo Active-Controlled Studies MN302 (12 months) Leflunomide (n=495)*51.131.1 9.9 Methotrexate (n=489)*65.243.816. 4 The best DMARD for inflammation between Arava (leflunomide) and Methotrexate is Methotrexate, as it showed higher ACR50 and ACR70 response rates in the MN302 study (65.2% and 43.8% respectively) compared to leflunomide (51.1% and 31.1% respectively) 2.

• Key points:
  • ACR50 response rate: Methotrexate (65.2%) vs Leflunomide (51.1%)
  • ACR70 response rate: Methotrexate (43.8%) vs Leflunomide (31.1%)

From the Research

Comparison of DMARDs for Inflammation

• Arava (leflunomide) and methotrexate are both disease-modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis (RA) and other forms of inflammatory arthritis.
• Methotrexate is generally considered the first-line treatment for RA due to its efficacy and safety profile 3, 4.
• Studies have shown that folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of methotrexate in patients with RA 5, 6, 7.
• Methotrexate has multiple mechanisms of action, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, and signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway 3.
• Arava (leflunomide) is an alternative DMARD that can be used in patients who are intolerant or unresponsive to methotrexate, but there is limited direct comparison between the two drugs in terms of efficacy and safety.

Efficacy and Safety of Methotrexate

• Methotrexate has been shown to be effective in reducing disease activity and slowing joint damage in patients with RA 3, 4.
• Folate supplementation can reduce the incidence of gastrointestinal side-effects and hepatotoxicity associated with methotrexate therapy 5, 6, 7.
• Methotrexate is generally well-tolerated, but can have rare but serious side-effects such as liver toxicity and cytopenias 4.

Comparison with Arava

• There is limited direct comparison between methotrexate and Arava (leflunomide) in terms of efficacy and safety.
• Arava (leflunomide) is an alternative DMARD that can be used in patients who are intolerant or unresponsive to methotrexate.
• Further studies are needed to determine the relative efficacy and safety of methotrexate and Arava (leflunomide) in the treatment of RA and other forms of inflammatory arthritis.